The aim of this LEAD application is to test the value of examining cellular and molecular abnormalities in extra-neural tissues from patients with Alzheimer's disease (DAT). It will test whether or not reported abnormalities relate to the presence of the clinical syndrome of DAT or certain of its subgroups (familial vs. sporadic, early vs. late onset, with vs. without Parkinsonism, myoclonus, depression, or early aphasia). DAT patients and disease and intact controls of comparable age and sex will all receive detailed examination including neuropsychological testing; follow- up where possible will be to autopsy. Skin cell cultures including biopsy will be meticulously standardized to ensure that DAT and control cells are studied under identical conditions including identical biological age in culture. Parameters measured in the cultures will include two related to the materials which accumulate in DAT brain: amyloid precursor protein, and materials which react with antibodies to paired helical filaments (PHF). (Recent studies by the PI and co-workers indicate that skin cells accumulate anti-PHF reactive materials when grown under specified conditions, much more in DAT cells than in controls.) Other parameters to be measured have been reported abnormal in DAT cells in at least two laboratories: isoproterenol-stimulated cyclic AMP synthesis, cellular calcium homeostasis, and [U-14C] glutamine oxidation. Data will be stored in a relational data base (SIR-software) and relations among clinical and laboratory findings analyzed in detail (SAS statistical software). Dr. Ronald Black, an assistant professor of Neurology, will develop methods to quantitate anti-PHF reactive materials, compare the amounts of these materials in soluble and insoluble fractions of affected and unaffected areas of DAT and control brains, and then compare their amounts in cultured DAT and control cells. He will gain expertise in clinical as well as laboratory research in dementias by participating actively in the clinical evaluations. One pilot study will examine a possible increase in anti-APP reactive materials in DAT granulocytes, and a second possible abnormalities in phosphokinase activities in cultured DAT skin cells. Future pilots will also study other potential markers. The proposed investigations will extend the PI's ongoing mechanistic studies of abnormalities in cultured DAT cells. They will test directly whether or not the abnormalities studied relate closely to the clinical syndrome of DAT or to DAT subgroups.